Therapeutic preparation and process of making and using it



Jan. 10, 1939.

D. A. SCOTT ET AL.

THERAPEUTIC PREPARATION AND PROCESS OF MAKING 'AND UISING IT Filed spt. 26. 195e Wx B QQ Ni Sk T .N- 2 m Q n Q In. T m. M H Q 4 OOO l l l omg.

BY T l,

,ATTORNEYS Patented Jan. 10, 1939 Unirse stares i PATENT OFFICE THERAPEUTICPREPARATION AND PROCESS F MAKING AND USING IT Application September 26, 1936, Serial No. 102,794

2 Claims.

It is the object of our invention to effect prolongation of the blood-sugar-lowering action of Insulin; and to make such action lmore nearly uniform over a considerable period of time, and

5 to obtain a more effective utilization of Insulin.

We do this by subcutaneously administering with the Insulin an amount of zinc much greater in proportion to the Insulin than that found in crystals of Insulin obtained with Zinc.

It is known (Delezenne, 1919;l Lutz, 1926; Scott and Fisher, 1935) that zinc exists in the pancreas. One of us (Scott) has discovered that the copresence -with Insulin of certain metals is necessary for obtaining crystals of Insulin with certainty and high yields; and his application Serial No. 102,795, filed September 26, 1936, is based on that discovery. Among such metals is zinc.

However, the amount of zinc in crystals of Insulin obtained with zinc (which crystals we shall for convenience refer to as zinc crystals of Insulin) does not exceed about 0.5% of the dry weight of the Insulin and with only such a percentage of zinc co-present with it, Insulin has substantially its usual and familiar blood-sugarlowering action. In `that usual and'familiar action, in rabbits for instance, there is a fairly sharp peak effect of the Insulin, in the lowering of blood-sugar levels, usually within a half hour to two and a half hours after 'subcutaneous administration of the Insulin; and the greater part of the effect usually disappears ,within about ve to eight hours after the injection.

We have discovered that by having a much greater amount of zinc present with Insulin, the action of the Insulin when subcutaneously Aadministered is modified so that the period of lowering of blood-sugar levels is markedly prolonged, generally with a less sharp peak effect and a greater total effect.

any convenient manner, as by adding, to the Insulin, zinc in metallic form, or in the form of any suitable compound, such as zinc chloride', zinc acetate, zinc sulphate, or zinc oxide; and we intend to include any suitable zinc compounds when we speak of adding zinc. Sufficient zinc maybe obtained by a sufliciently long contact of Insulin solutions with vessels or equipment made of or containing zinc. Also, the zinc may be simply added to any solid preparation of Insulin so that it goes yinto solution when a solution of the Insulin is made.

We administer with Insulin an amount of zinc which in proportion to the dry weight of the i 'Insulin' is many times greater than the approxi- 'I'he desired amount of zinc may be provided in (o1. 1er- 75) y mately 0.5% found in zinc crystals of Insulin. That is what we meanby administering excess zinc. To produce the desired prolongation of Insulin action, the amount of zinc in proportion to Insulin may be varied within wide limits, and varies from one. species of animal to another; but' we have found it convenient that it be between 25% and 500% of the dry weight of the Insulin. A very effective amount of zinc is an amount somewhat in excess of the dry weightof the Insulin, or between 100% and 200% thereof.

When we speak of dry weight of Insulin, we mean to refer either to crystals of Insulin which contain about 22 units per mg.) or to dry amorphous commercial preparations of Insulin (which usually contain from about `to about 22 units per mg). In the comparisons illustrated by the curves of the accompanying drawing, we have for convenience used a preparation of Insulin which contains about units per mg. ,in its dry amorphous form.

The comparative blood-sugar-lowering effects of a solution containing Insulin and excess zinc, and of an ordinary solution of Insulin, as subcutaneously administered to rabbits," are illustrated in the accompanying drawing. The single figure of such drawing is a diagram showing two curves, in dotted and full lines respectively; which show the average blood-sugar values of two similar groups, of twenty rabbits each, over a period of twelve hours following subcutaneous injection of an 'ordinary solution of Insulin (dotted-line curve) and of a solution containing Insulin andl excess zinc (full-line curve). In each of these solutions the concentration of Insulin was 40 units (about 2 mg.) per cc; and in the second the concentration of zinc was about 3 mg. per cc, or 7.5 mg. per 100 units of Insulin.

When the injection was of the ordinary solution of Insulin (two units per kilogram of body weight of the rabbit), as indicated by the dottedline curve the level of average blood-sugar values dropped from a normal of about 0.120% to a value of about 0.057% in about two hours, and then rose fairly rapidly until at the end of about seven hours it had returned almost to normal. l

In contrast to this was the effect, shown by the f its minimum until about ave hours after the injection.- After that minimum was reached, the

level rose at a relatively slow rate, so that at the end of seven hours it had risen to only about 0.065%, and at the end of ten hours only to about 0.086%. Y

In using a solution containing `fInsulin and excess zinc, in accordance with our`invention, it is desirable for many reasons that the solution have a hydrogen ion concentration on vthe acid side of the isoelectric point of 'Insulin'. which is around'pH 4.8 to 11H55. We have gotten exceilent results at pH 2.5 to pH 3.5.

We are notsure what if any chemical ier physical combination takes place between the Insulin and the zinc. Whether or not any such combination occurs, physiological action such as we have outlined is attained. f

Our solution containing Insulin and encess amasar zinc not only produces a prolonged eeet upon subcutaneous or intramuscular injection, but also produces a greater metabolism of sugar per unit of Insuiin, with a less sharp peak effect; which is clear from the curves of the diagram. As a result, larger doses of it may be administered, the number of doses per day may be reduced, and the total daily requirement of Insulin is usually decreased.

We claim as our invention:

1. A therapeutic preparation, comprising Insulin mixed with an amount of zinc which is between 25% and 500% of the dry weight of the Insulin.

2. A therapeutic preparation, comprising Insulin mixed with zinc in an amount in excess of the dry weight of the `r 

